Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Toonen, Lodewijk J.A.; Overzier, Maurice; Evers, Melvin M.; León, Leticia G.; Zeeuw, Sander A.J. van der; Mei, Hailiang; Kiełbasa, Szymon M.; Goeman, Jelle J.; Hettne, Kristina; Magnússon, Ólafur Þ.; Poirel, Marion; Seyer, Alexandre; Hoen, Peter A.C. ‘t; Roon‐Mom, Willeke M. C. van

doi:10.1186/s13024-018-0261-9

Cited by 49 publications

(56 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A high number of downregulated genes in both, the KI mice and humans were enriched for this cell type. These findings are in line with the transcriptomic studies of Ramani et al (2017) and Toonen et al (2018) in the YAC84Q mice, with oligodendrocytes appearing mainly affected by transcriptional changes. Ramani and colleagues further showed that ATXN3 is present in the cell nuclei of oligodendrocytes.…”

Section: Discussionsupporting

confidence: 89%

“…While Shakkottai et al (2011) reported of changes in Purkinje cell firing concurring with behavioral deficits in YAC84Q mice even before observable neurodegeneration was detected, Costa Mdo et al (2013) described behavioral deficits in the same mouse model, but could not detect changes in Purkinje cell count. Toonen et al (2018) did not observe behavioral differences at the same time point. Therefore, the relation between Purkinje cell loss and a motor phenotype needs further investigation in several SCA3 models.…”

Section: Discussionmentioning

confidence: 62%

“…In line with two other SCA3 rodent models, Interleukin-33 (Il33) is persistently downregulated in cerebellar samples of the 304Q/304Q KI mice at both investigated time points (2 and 12-months of age). In YAC84Q mice the Il33 transcript is also downregulated in brain stem samples of 6-month-old SCA3 mice (Ramani et al 2017) and whole brain samples of 17.5-month-old mice (Toonen et al 2018). In addition to this, Il33 shows highest expression levels in the central nervous system, being constitutively expressed in astrocytes, microglia, and oligodendrocytes (Liew et al 2016).…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, the late-onset behavior phenotype in the hemizygous SCA3 YAC84Q model, which expresses a full-length copy of human cDNA containing 84 CAG repeats in the ATXN3 gene with all regulatory elements (Cemal et al 2002), was often not reproducible in follow-up studies (Toonen et al 2018, Weber et al 2020. This leads us to the assumption, that to trigger a phenotype comparable to human patients, a hyper-expansion of the polyQ tract is necessary.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

Haas

Incebacak

Hentrich

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction), and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism.Methods: Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model. Results:The novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes. Conclusion:The novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

Haas

Incebacak

Hentrich

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The comparison of both stages identified 54 genes with progressively changed expression during the disease course, including conspicuously strong downregulations for several enzymes of cholesterol biogenesis. It is crucial to note that also in a mouse model of SCA3 (Machado-Joseph disease), recent global transcriptome profiling demonstrated a significant enrichment of cholesterol biogenesis dysregulations in brainstem, but increased levels of ceramides, di- and triglycerides in blood [204]. Furthermore, for SCA3 it was shown that restoration of brain cholesterol homeostasis has therapeutic potential [131].…”

Section: Discussionmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

View full text Add to dashboard Cite

Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

show abstract

Pathogenic mechanisms underlying spinocerebellar ataxia type 1

Tejwani

Lim

2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The family of hereditary cerebellar ataxias is a large group of disorders with heterogenous clinical manifestations and genetic etiologies. Among these, over 30 autosomal dominantly inherited subtypes have been identified, collectively referred to as the spinocerebellar ataxias (SCAs). Generally, the SCAs are characterized by a progressive gait impairment with classical cerebellar features, and in a subset of SCAs, accompanied by extra-cerebellar features. Beyond the common gait impairment and cerebellar atrophy, the wide range of additional clinical features observed across the SCAs is likely explained by the diverse set of mutated genes that encode proteins with seemingly disparate functional roles in nervous system biology. By synthesizing knowledge obtained from studies of the various SCAs over the past several decades, convergence onto a few key cellular changes, namely ion channel dysfunction and transcriptional dysregulation, has become apparent and may represent central mechanisms of cerebellar disease pathogenesis. This review will detail our current understanding of the molecular pathogenesis of the SCAs, focusing primarily on the first described autosomal dominant spinocerebellar ataxia, SCA1, as well as the emerging common core mechanisms across the various SCAs.

show abstract

Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Cited by 49 publications

References 83 publications

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Pathogenic mechanisms underlying spinocerebellar ataxia type 1

Contact Info

Product

Resources

About